The present invention relates to a pharmaceutical composition comprising a bicyclic pyridinol derivative for preventing or treating diseases caused by angiogenesis.
Angiogenesis is a process of forming new capillary blood vessels from pre-existing microvessels. Angiogenesis normally occurs during embryonic development, tissue regeneration, wound healing, and corpus luteum development that is a cyclical change in female reproductive system; in any case, angiogenesis is strictly regulated to progress (Folkman J et al., Int. Rev. Exp. Pathol., 16, pp207-248, 1976).
The vascular endothelial cells are growing slowly and do not divide well relatively as compared with other types of cells in adult body. Angiogenesis is a process that generally includes degradation of a vascular basement membrane by proteases released by stimuli of proangiogenic factors; migration and proliferation of vascular endothelial cells; tubular formation due to differentiation of vascular endothelial cells; reconstruction of blood vessels; and generation of new capillary blood vessels.
However, there are diseases induced by angiogenesis that is not regulated autonomously but grows morbidly. Such diseases associated with angiogenesis occurring in pathological conditions include hemangioma, angiofibroma, vascular malformation and cardiovascular diseases, such as arteriosclerosis, vascular adhesion, and scleroedema. Ocular diseases associated with angiogenesis include corneal graft angiogenesis, neovascular glaucoma, diabetic retinopathy, corneal diseases induced by new blood vessels, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia, granular conjunctivitis, and the like. Furthermore, angiogenesis-related diseases may include chronic inflammatory diseases such as arthritis, cutaneous diseases such as psoriasis, capillarectasia, pyogenic granuloma, seborrheic dermatitis, acne, Alzheimer's disease, and obesity. Tumor growth and metastases are necessarily dependent on angiogenesis (D'Amato R J et al., Ophthalmology, 102(9), pp1261-1262, 1995; Arbiser J L, J. Am. Acad. Dermatol., 34(3), pp486-497, 1996; O'Brien K D et al. Circulation, 93(4), pp672-682, 1996; Hanahan D et al., Cell, 86, pp353-364, 1996).
Especially, angiogenesis plays an important role in growth and metastasis of cancer cells. Tumor is supplied with nutrition and oxygen necessary for growth and proliferation through new blood vessels, and the new blood vessels infiltrating into the tumor allow the cancer cells being metastasized to enter the blood circulation system and thus support metastasis of the cancer cells (Folkman and Tyler, Cancer Invasion and metastasis, Biologic mechanisms and Therapy (S. B. Day ed.) Raven press, New York, pp94-103, 1977; Polverini P J, Crit. Rev. Oral. Biol. Med., 6(3), pp230-247, 1995). The major cause of death in cancer patients is metastasis, and the reasons why the chemotherapies or immunotherapies being used clinically at present do not contribute to an increase in a survival rate of cancer patients is directed to metastasis of cancer.
Arthritis, a typical disease in inflammatory diseases, is initiated as an autoimmune disorder. Along with progression of the disease, chronic inflammation occurring in the synovial cavity between joints induces angiogenesis to destroy the cartilage. That is, proliferations of synovial cells and vascular endothelial cells in the synovial cavity are activated by cytokines that induce inflammations, resulting in development of angiogenesis. Finally, the articular cartilage playing a role of a cushion is destroyed by articular pannus as a connective tissue layer formed in a cartilaginous part (Koch A E et al., Arthritis. Rheum., 29, pp471-479, 1986; Stupack D G et al., Braz J. Med. Biol. Res., 32(5), pp578-581, 1999; Koch A E, Atrhritis. Rheum., 41(6), pp951-962, 1998).
Many ocular diseases, from which millions of people are losing their eyesight all over the world every year, result mainly from angiogenesis (Jeffrey M I et al., J. Clin. Invest., 103, pp1231-1236, 1999). Typical diseases resulting from angiogenesis include macular degeneration, diabetic retinopathy, and the like that occur commonly in old age, premature infant's retinopathy, neovascular glaucoma, corneal diseases induced by new blood vessels, and the like (Adamis A P et al., Angiogenesis, 3, pp9-14, 1999). Among them, diabetic retinopathy that is one of the diabetic complications and a disease that retinal capillaries invade vitreous body to become blind.
Psoriasis characterized by red spots and scaly skin is a chronic proliferative disease occurring in skin and is accompanied with pain and malformation. Normally, keratinocytes proliferate once a month, however, in a psoriasis patient, the keratinocytes proliferate at least once a week. For such rapid proliferation, a large quantity of blood is required, resulting in active angiogenesis (Folkman J, J. Invest. Dermatol., 59, pp40-48, 1972).
Since it is possible to apply angiogenesis inhibitors to agents for treating various diseases associated with angiogenesis, in recent years, a variety of studies aimed at treating such diseases by inhibiting angiogenesis have been actively conducted. Since such angiogenesis inhibitors should be administrated to patients for a long time, the most ideal inhibitor is one that should have low toxicity and can be orally administrated. Accordingly, there has been a demand for development of drugs that have low toxicity as angiogenesis inhibitors.